title: Desmosomal cadherins are decreased in explanted arrhythmogenic right ventricular dysplasia/cardiomyopathy patient hearts.
abstract: OBJECTIVE
  Arrhythmogenic right ventricular Dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited cardiomyopathy associated with ventricular arrhythmia, heart failure and sudden death. Genetic studies have demonstrated the central role of desmosomal proteins in this disease, where 50% of patients harbor a mutation in a desmosmal gene. However, clinical diagnosis of the disease remains difficult and molecular mechanisms appears heterogeneous and poorly understood. The aim of this study was to characterize the expression profile of desmosomal proteins in explanted ARVD/C heart samples, in order to identify common features of the disease.
  
  
  RESULTS
  We examined plakophilin-2, desmoglein-2, desmocollin-2, plakoglobin and β-catenin protein expression levels from seven independent ARVD/C heart samples compared to two ischemic, five dilated cardiomyopathy and one healthy heart sample as controls. Ventricular and septum sections were examined by immunoblot analysis of total heart protein extracts and by immunostaining. Immunoblots indicated significant decreases in desmoglein-2 and desmocollin-2, independent of any known underlying mutations, whereas immune-histochemical analysis showed normal localization of all desmosomal proteins. Quantitative RT-PCR revealed normal DSG2 and DSC2 mRNA transcript levels, suggesting increased protein turn-over rather than transcriptional down regulation.
  
  
  CONCLUSIONS
  Reduced cardiac desmoglein-2 and desmocollin-2 levels appear to be specifically associated with ARVD/C, independent of underlying mutations. These findings highlight a key role of desmosomal cadherins in the pathophysiology of ARVD/C. Whether these reductions could be considered as specific markers for ARVD/C requires replication analysis.
authors.affiliation: UPMC, University Paris 06, Hôpital Pitié-Salpêtrière, Paris, France ; INSERM, UMR_S956, ICAN, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Alexia
authors.initials: A
authors.lastname: Vite
authors.forename: Estelle
authors.initials: E
authors.lastname: Gandjbakhch
authors.forename: Catherine
authors.initials: C
authors.lastname: Prost
authors.forename: Veronique
authors.initials: V
authors.lastname: Fressart
authors.forename: Pierre
authors.initials: P
authors.lastname: Fouret
authors.forename: Nathalie
authors.initials: N
authors.lastname: Neyroud
authors.forename: Françoise
authors.initials: F
authors.lastname: Gary
authors.forename: Erwan
authors.initials: E
authors.lastname: Donal
authors.forename: Shaida
authors.initials: S
authors.lastname: Varnous
authors.forename: Guy
authors.initials: G
authors.lastname: Fontaine
authors.forename: Paul
authors.initials: P
authors.lastname: Fornes
authors.forename: Françoise
authors.initials: F
authors.lastname: Hidden-Lucet
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
authors.forename: Philippe
authors.initials: P
authors.lastname: Charron
authors.forename: Eric
authors.initials: E
authors.lastname: Villard
mesh_terms: D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D051187:Desmocollins / Q000378:metabolism*; D051301:Desmoglein 2 / Q000378:metabolism*; D051180:Desmoplakins / Q000378:metabolism; D051181:Desmosomal Cadherins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D015151:Immunoblotting; D008854:Microscopy, Electron; D051191:Plakophilins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D051176:beta Catenin / Q000378:metabolism; D051185:gamma Catenin
chemical_list: D015415:Biomarkers; D017931:DNA Primers; C081561:DSC2 protein, human; D051187:Desmocollins; D051301:Desmoglein 2; D051180:Desmoplakins; D051181:Desmosomal Cadherins; C495292:JUP protein, human; C495337:PKP2 protein, human; D051191:Plakophilins; D051176:beta Catenin; D051185:gamma Catenin